Robust Radicals Featuring B- and N-Embedded Dioxygen-Bridged Units: Synthesis, Structures, and Optical Properties.

Tris(2,4,6-trichlorophenyl)methyl (TTM) group has been widely used for constructing organic radicals, but the poor optical stabilities limit the application prospects of the TTM radicals. In this work, the rigid B- and N-embedded dioxygen-bridged (BO and NO) units were attached to the TTM skeleton as the strong electron-withdrawing and electron-donating groups, respectively. The rigidity and strong electronic effect of the BO and NO units contribute to the high chemical and optical stability of BO-TTM and NO-TTM radicals. Notably, NO-TTM exhibits near-infrared emission at 830 nm with a narrow full width at half maximum (FWHM) of 55 nm (100 meV), while BO-TTM shows blue-shifted luminescence at 635 nm and a narrower FWHM of merely 43 nm (130 meV). This study has developed a methodology to produce highly efficient and enduring luminescent radicals, which could tune emission properties such as wavelength and FWHM.

Plant-derived flavonoids are a potential source of drugs for the treatment of liver fibrosis.

Liver fibrosis is a dynamic pathological process that can be triggered by any chronic liver injury. If left unaddressed, it will inevitably progress to the severe outcomes of liver cirrhosis or even hepatocellular carcinoma. In the past few years, the prevalence and fatality of hepatic fibrosis have been steadily rising on a global scale. As a result of its intricate pathogenesis, the quest for pharmacological interventions targeting liver fibrosis has remained a formidable challenge. Currently, no pharmaceuticals are exhibiting substantial clinical efficacy in the management of hepatic fibrosis. Hence, it is of utmost importance to expedite the development of novel therapeutics for the treatment of this condition. Various research studies have revealed the ability of different natural flavonoid compounds to alleviate or reverse hepatic fibrosis through a range of mechanisms, which are related to the regulation of liver inflammation, oxidative stress, synthesis and secretion of fibrosis-related factors, hepatic stellate cells activation, and proliferation, and extracellular matrix synthesis and degradation by these compounds. This review summarizes the progress of research on different sources of natural flavonoids with inhibitory effects on liver fibrosis over the last decades. The anti-fibrotic effects of natural flavonoids have been increasingly studied, making them a potential source of drugs for the treatment of liver fibrosis due to their good efficacy and biosafety.

Discovery of CBPD-268 as an Exceptionally Potent and Orally Efficacious CBP/p300 PROTAC Degrader Capable of Achieving Tumor Regression.

CBP/p300 proteins are key epigenetic regulators and promising targets for the treatment of castration-resistant prostate cancer and other types of human cancers. Herein, we report the discovery and characterization of CBPD-268 as an exceptionally potent, effective, and orally efficacious PROTAC degrader of CBP/p300 proteins. CBPD-268 induces CBP/p300 degradation in three androgen receptor-positive prostate cancer cell lines, with DC50 ≤ 0.03 nM and Dmax > 95%, leading to potent cell growth inhibition. It has an excellent oral bioavailability in mice and rats. Oral administration of CBPD-268 at 0.3-3 mg/kg resulted in profound and persistent CBP/p300 depletion in tumor tissues and achieved strong antitumor activity in the VCaP and 22Rv1 xenograft tumor models in mice, including tumor regression in the VCaP tumor model. CBPD-268 was well tolerated in mice and rats and displayed a therapeutic index of >10. Taking these results together, CBPD-268 is a highly promising CBP/p300 degrader as a potential new cancer therapy.

Assessment of sarcopenic obesity as a predictor of pneumonia in patients with stable schizophrenia-A prospective study.

OBJECTIVE: The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) recently released the first international consensus on the diagnostic criteria for Sarcopenic obesity (SO). The present study aimed to explore the ability of SO to predict the risk of pneumonia in patients with stable schizophrenia. METHODS: This was a prospective study involving hospitalized patients with schizophrenia aged ≥50 years from two mental health centers in western China. Baseline patient data were collected from September 1 to September 30, 2020. Follow-up data on pneumonia were collected from October 2020 to October 2022. The diagnosis of SO was based on the ESPEN/EASO criteria. Patients were assessed for handgrip strength (HGS), skeletal muscle mass/weight (SMM/W), and fat mass percentage (FM%). Logistic regression analysis was used to explore the effect of SO on the risk of pneumonia in patients with stable schizophrenia. RESULTS: A total of 320 patients with stable schizophrenia were included. Of these, 74 (23.13%) were diagnosed with SO, while 117 (36.56%) developed pneumonia. Compared with patients in the non-low HGS, non-low HGS + non-low SMM/W (or non-low HGS + low SMM/W or low HGS + non-low SMM/W) and non-SO groups, the proportions of patients with pneumonia in the low HGS (42.3% vs. 25.9%, p = 0.004), low HGS + low SMM/W (45.3% vs. 33.3%, p = 0.048), and SO (47.3% vs. 33.3%, p = 0.029) groups, respectively, were higher. However, there was no difference in the proportion of patients with pneumonia in the low SMM/W group and the obese group compared with the non-low SMM/W and non-obese groups. Further logistic regression analysis after adjustment for potential influencing factors showed that compared with the non-low HGS group, patients in the low HGS group had a higher risk of pneumonia (OR = 1.892, 95%CI: 1.096-3.264). CONCLUSION: SO defined according to the ESPEN/EASO criteria was not found to be significantly associated with the development of pneumonia in patients with stable schizophrenia. Further verification of these results is needed with larger sample sizes and the establishment of a cutoff value for this population.

Discovery of CBPD-409 as a Highly Potent, Selective, and Orally Efficacious CBP/p300 PROTAC Degrader for the Treatment of Advanced Prostate Cancer.

CBP/p300 are critical transcriptional coactivators of the androgen receptor (AR) and are promising cancer therapeutic targets. Herein, we report the discovery of highly potent, selective, and orally bioavailable CBP/p300 degraders using the PROTAC technology with CBPD-409 being the most promising compound. CBPD-409 induces robust CBP/p300 degradation with DC50 0.2-0.4 nM and displays strong antiproliferative effects with IC50 1.2-2.0 nM in the VCaP, LNCaP, and 22Rv1 AR+ prostate cancer cell lines. It has a favorable pharmacokinetic profile and achieves 50% of oral bioavailability in mice. A single oral administration of CBPD-409 at 1 mg/kg achieves >95% depletion of CBP/p300 proteins in the VCaP tumor tissue. CBPD-409 exhibits strong tumor growth inhibition and is much more potent and efficacious than two CBP/p300 inhibitors CCS1477 and GNE-049 and the AR antagonist Enzalutamide. CBPD-409 is a promising CBP/p300 degrader for further extensive evaluations for the treatment of advanced prostate cancer and other types of human cancers.

Association between cancer health literacy and cancer-related behavior of residents in Shandong, China.

Health literacy is closely related to the incidence of major chronic diseases and its related behaviors such as cancer-related behaviors. This study explored how the cancer health literacy level affects cancer-related behaviors. About one to two villages from six cities of Shandong province were selected as sample areas. Professionals conducted face-to-face interviews with the participants. Finally, 1200 residents completed 1085 effective questionnaires. Data were analysed from a cross-sectional survey in 2019, which included 1085 residents in six cities/counties of Shandong province, China. The result showed that residents with high cancer health literacy were more likely to eat fruits and vegetables frequently, avoid eating moldy food and take exercise. Besides, they were more likely to engage in health education and have a higher willingness to pay for cancer screenings. Most residents in Shandong province have a basic level of cancer health literacy. Improving the cancer health literacy of the population can be an effective strategy to promote a healthier lifestyle, thereby reducing the incidence rates related to cancers.

Deep learning-based algorithms for low-dose CT imaging: A review.

The computed tomography (CT) technique is extensively employed as an imaging modality in clinical settings. The radiation dose of CT, however, is significantly high, thereby raising concerns regarding the potential radiation damage it may cause. The reduction of X-ray exposure dose in CT scanning may result in a significant decline in imaging quality, thereby elevating the risk of missed diagnosis and misdiagnosis. The reduction of CT radiation dose and acquisition of high-quality images to meet clinical diagnostic requirements have always been a critical research focus and challenge in the field of CT. Over the years, scholars have conducted extensive research on enhancing low-dose CT (LDCT) imaging algorithms, among which deep learning-based algorithms have demonstrated superior performance. In this review, we initially introduced the conventional algorithms for CT image reconstruction along with their respective advantages and disadvantages. Subsequently, we provided a detailed description of four aspects concerning the application of deep neural networks in LDCT imaging process: preprocessing in the projection domain, post-processing in the image domain, dual-domain processing imaging, and direct deep learning-based reconstruction (DLR). Furthermore, an analysis was conducted to evaluate the merits and demerits of each method. The commercial and clinical applications of the LDCT-DLR algorithm were also presented in an overview. Finally, we summarized the existing issues pertaining to LDCT-DLR and concluded the paper while outlining prospective trends for algorithmic advancement.

B-embedded disulfide-bridged π-conjugated compounds: structures and optical tuning.

Two novel B-embedded disulfide-bridged π-conjugated compounds (BS-CZ and BS-N) bearing different electron donor groups (phenyl carbazole and triphenylamine) have been prepared and show different optical mechanisms. The compound BS-CZ exhibits significant multiple resonance thermal activation delayed fluorescence (MR-TADF) properties with a small singlet-triplet energy gap (ΔEST = 0.16 eV) and a narrow half-peak full width (FWHM = 33 nm), while the compound BS-N shows traditional fluorescence luminescence (FL) characteristics with a larger ΔEST (0.28 eV) and FWHM (57 nm). Time-dependent density functional theory (TD-DFT) calculations show that the lowest excited singlet state (S1) of the compound BS-CZ exhibits local excited (LE) state characteristics, while the charge transfer (CT) state characteristics can be found in S1 of the compound BS-N. Considering good optical performance, the compound BS-CZ is used as an emitting layer of the organic light-emitting diode device and achieved saturated blue emission (473 nm) with a narrow FWHM (39 nm), and CIE color coordinates of (0.12, 0.21). This work provides an important strategy for the optical mechanism regulation and photoelectric applications of B-embedded disulfide-bridged π-conjugated molecules.

Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function.

Impaired autophagy is known to cause mitochondrial dysfunction and heart failure, in part due to altered mitophagy and protein quality control. However, whether additional mechanisms are involved in the development of mitochondrial dysfunction and heart failure in the setting of deficient autophagic flux remains poorly explored. Here, we show that impaired autophagic flux reduces nicotinamide adenine dinucleotide (NAD+) availability in cardiomyocytes. NAD+ deficiency upon autophagic impairment is attributable to the induction of nicotinamide N-methyltransferase (NNMT), which methylates the NAD+ precursor nicotinamide (NAM) to generate N-methyl-nicotinamide (MeNAM). The administration of nicotinamide mononucleotide (NMN) or inhibition of NNMT activity in autophagy-deficient hearts and cardiomyocytes restores NAD+ levels and ameliorates cardiac and mitochondrial dysfunction. Mechanistically, autophagic inhibition causes the accumulation of SQSTM1, which activates NF-κB signaling and promotes NNMT transcription. In summary, we describe a novel mechanism illustrating how autophagic flux maintains mitochondrial and cardiac function by mediating SQSTM1-NF-κB-NNMT signaling and controlling the cellular levels of NAD+.

Geometric and Electronic Engineering in Co/VN Nanoparticles to Boost Bifunctional Oxygen Electrocatalysis for Aqueous/Flexible Zn-Air Batteries.

Modulating metal-metal and metal-support interactions is one of the potent tools for augmenting catalytic performance. Herein, highly active Co/VN nanoparticles are well dispersed on three-dimensional porous carbon nanofoam (Co/VN@NC) with the assistance of dicyandiamide. Studies certify that the consequential disordered carbon substrate reinforces the confinement of electrons, while the coupling of diverse components optimizes charge redistribution among species. Besides, theoretical analyses confirm that the regulated electron configuration can significantly tune the binding strength between the active sites and intermediates, thus optimizing reaction energy barriers. Therefore, Co/VN@NC exhibits a competitive potential difference (ΔE, 0.65 V) between the half-wave potential of ORR and OER potential at 10 mA cm-2, outperforming Pt/C+RuO2 (0.67 V). Further, catalyst-based aqueous/flexible ZABs present superior performances with peak power densities of 156 and 85 mW cm-2, superior to Pt/C-based counterparts (128 and 73 mW cm-2). This research provides a pivotal foundation for the evolution of bifunctional catalysts in the energy sector.

Construction and validation of a nomogram to predict the overall survival of small cell lung cancer: a multicenter retrospective study in Shandong province, China.

BACKGROUND: Patients diagnosed with small cell lung cancer (SCLC) typically experience a poor prognosis, and it is essential to predict overall survival (OS) and stratify patients based on distinct prognostic risks. METHODS: Totally 2309 SCLC patients from the hospitals in 15 cities of Shandong from 2010 - 2014 were included in this multicenter, population-based retrospective study. The data of SCLC patients during 2010-2013 and in 2014 SCLC were used for model development and validation, respectively. OS served as the primary outcome. Univariate and multivariate Cox regression were applied to identify the independent prognostic factors of SCLC, and a prognostic model was developed based on these factors. The discrimination and calibration of this model were assessed by the time-dependent C-index, time-dependent receiver operator characteristic curves (ROC), and calibration curves. Additionally, Decision Curve Analysis (DCA) curves, Net Reclassification Improvement (NRI), and Integrated Discriminant Improvement (IDI) were used to assess the enhanced clinical utility and predictive accuracy of the model compared to TNM staging systems. RESULTS: Multivariate analysis showed that region (Southern/Eastern, hazard ratio [HR] = 1.305 [1.046 - 1.629]; Western/Eastern, HR = 0.727 [0.617 - 0.856]; Northern/Eastern, HR = 0.927 [0.800 - 1.074]), sex (female/male, HR = 0.838 [0.737 - 0.952]), age (46-60/≤45, HR = 1.401 [1.104 - 1.778]; 61-75/≤45, HR = 1.500 [1.182 - 1.902]; >75/≤45, HR = 1.869 [1.382 - 2.523]), TNM stage (II/I, HR = 1.119[0.800 - 1.565]; III/I, HR = 1.478 [1.100 - 1.985]; IV/I, HR = 1.986 [1.477 - 2.670], surgery (yes/no, HR = 0.677 [0.521 - 0.881]), chemotherapy (yes/no, HR = 0.708 [0.616 - 0.813]), and radiotherapy (yes/no, HR = 0.802 [0.702 - 0.917]) were independent prognostic factors of SCLC patients and were included in the nomogram. The time-dependent AUCs of this model in the training set were 0.699, 0.683, and 0.683 for predicting 1-, 3-, and 5-year OS, and 0.698, 0.698, and 0.639 in the validation set, respectively. The predicted calibration curves aligned with the ideal curves, and the DCA curves, the IDI, and the NRI collectively demonstrated that the prognostic model had a superior net benefit than the TNM staging system. CONCLUSION: The nomogram using SCLC patients in Shandong surpassed the TNM staging system in survival prediction accuracy and enabled the stratification of patients with distinct prognostic risks based on nomogram scores.

Lignans as multi-targeted natural products in neurodegenerative diseases and depression: Recent perspectives.

As the global population ages, the treatment of neurodegenerative diseases is becoming more and more important. There is an urgent need to discover novel drugs that are effective in treating neurological diseases. In recent years, natural products and their biological activities have gained widespread attention. Lignans are a class of metabolites extensively present in Chinese herbal medicine and possess good pharmacological effects. Latest studies have demonstrated their neuroprotective pharmacological activity in preventing acute/chronic neurodegenerative diseases and depression. In this review, the pharmacological effects of these disorders, the pharmacokinetics, safety, and clinical trials of lignans were summarized according to the scientific literature. These results proved that lignans mainly exert antioxidant and anti-inflammatory activities. Anti-apoptosis, regulation of nervous system functions, and modulation of synaptic signals are also potential effects. Despite the substantial evidence of the neuroprotective potential of lignans, it is not sufficient to support their use in the clinical management. Our study suggests that lignans can be used as prospective agents for the treatment of neurodegenerative diseases and depression, with a view to informing their further development and utilization.

Deficiency of endothelial sirtuin1 in mice stimulates skeletal muscle insulin sensitivity by modifying the secretome.

Downregulation of endothelial Sirtuin1 (Sirt1) in insulin resistant states contributes to vascular dysfunction. Furthermore, Sirt1 deficiency in skeletal myocytes promotes insulin resistance. Here, we show that deletion of endothelial Sirt1, while impairing endothelial function, paradoxically improves skeletal muscle insulin sensitivity. Compared to wild-type mice, male mice lacking endothelial Sirt1 (E-Sirt1-KO) preferentially utilize glucose over fat, and have higher insulin sensitivity, glucose uptake, and Akt signaling in fast-twitch skeletal muscle. Enhanced insulin sensitivity of E-Sirt1-KO mice is transferrable to wild-type mice via the systemic circulation. Endothelial Sirt1 deficiency, by inhibiting autophagy and activating nuclear factor-kappa B signaling, augments expression and secretion of thymosin beta-4 (Tß4) that promotes insulin signaling in skeletal myotubes. Thus, unlike in skeletal myocytes, Sirt1 deficiency in the endothelium promotes glucose homeostasis by stimulating skeletal muscle insulin sensitivity through a blood-borne mechanism, and augmented secretion of Tß4 by Sirt1-deficient endothelial cells boosts insulin signaling in skeletal muscle cells.

Effect of perylene assembly shapes on photoelectrochemical properties and ultrasensitive biosensing behaviors toward dopamine.

In this study, a photoelectrochemical (PEC) sensor based on perylene diimide derivatives (PDIs) was developed for the ultrasensitive quantification of dopamine (DA). PDIs were able to form self-assembled semiconductor nanostructures by strong π-π stacking, suitable for photoactive substances. Moreover, the shape of the PDI significantly affected the PEC properties of these nanostructures. The results showed that amino PDI with two-dimensional (2D) wrinkled layered nanostructures exhibited superior PEC properties relative to one-dimensional (1D) nanorods and fiber-based nanostructures (methyl and carboxyl PDIs). Based on these results, a mechanism for PEC sensor action was then proposed. The presence of 2D amino-PDI resulted in accelerated charge separation and transport. Furthermore, dopamine acted as effective electron donor to cause an increase in photocurrent. The as-obtained sensor was then used to detect small molecules like DA. A blue light optimized sensor at an applied potential of 0.7 V showed a detection limit of 1.67 nM with a wide linear range of 5 nM to 10 µM. On the other hand, the sensor presented acceptable reliability in determining DA in real samples. A recovery rate between 97.99 and 101.0% was obtained. Overall, controlling the morphology of semiconductors can influence PEC performance, which is a useful finding for the future development of PEC sensors.

Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity.

Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite the development of several effective therapies targeting ERα signaling, clinical resistance remains a major challenge. In this study, we report the discovery of a new class of potent and orally bioavailable ERα degraders using the PROTAC technology, with ERD-3111 being the most promising compound. ERD-3111 exhibits potent in vitro degradation activity against ERα and demonstrates high oral bioavailability in mice, rats, and dogs. Oral administration of ERD-3111 effectively reduces the levels of wild-type and mutated ERα proteins in tumor tissues. ERD-3111 achieves tumor regression or complete tumor growth inhibition in the parental MCF-7 xenograft model with wild-type ER and two clinically relevant ESR1 mutated models in mice. ERD-3111 is a promising ERα degrader for further extensive evaluations for the treatment of ER+ breast cancer.

A comprehensive perspective on the interaction between gut microbiota and COVID-19 vaccines.

The efficacy of COVID-19 vaccines varies between individuals and populations, and the reasons for this are still not fully understood. Recent clinical studies and animal models have indicated that the gut microbiota may influence the immunogenicity of the vaccine and, thus, its effectiveness. This suggests that there is a bidirectional relationship between the gut microbiota and the COVID-19 vaccine, with the varying components of the microbiota either enhancing or reducing the vaccine's efficacy. To put an end to the spread of the COVID-19 pandemic, the necessity of vaccines that create powerful and long-term immunity is now more important than ever, and understanding the role of the gut microbiota in this process is essential. Conversely, COVID-19 vaccines also have a significant effect on the gut microbiota, decreasing its total number of organisms and the variety of species present. In this Review, we analyze the evidence that suggesting an interaction between the gut microbiota and COVID-19 vaccine effectiveness, consider the immunological mechanisms that may be responsible for this connection, and explore the possibility of using gut microbiota-focused interventions to improve the efficacy of COVID-19 vaccines.

Public Preference Heterogeneity and Predicted Uptake Rate of Upper Gastrointestinal Cancer Screening Programs in Rural China: Discrete Choice Experiments and Latent Class Analysis.

BACKGROUND: Rapid increases in the morbidity and mortality of patients with upper gastrointestinal cancer (UGC) in high-incidence countries in Asia have raised public health concerns. Screening can effectively reduce the incidence and mortality of patients with UGC, but the low population uptake rate seriously affects the screening effect. OBJECTIVE: We aimed to determine the characteristics that influence residents' preference heterogeneity for a UGC-screening program and the extent to which these characteristics predict residents' uptake rates. METHODS: A discrete choice experiment was conducted in 1000 residents aged 40-69 years who were randomly selected from 3 counties (Feicheng, Linqu, and Dongchangfu) in Shandong Province, China. Each respondent was repeatedly asked to choose from 9 discrete choice questions of 2 hypothetical screening programs comprising 5 attributes: screening interval, screening technique, regular follow-up for precancerous lesions, mortality reduction, and out-of-pocket costs. The latent class logit model was used to estimate residents' preference heterogeneity for each attribute level, their willingness to pay, and the expected uptake rates. RESULTS: Of the 1000 residents invited, 926 (92.6%) were included in the final analyses. The mean age was 57.32 (SD 7.22) years. The best model contained 4 classes of respondents (Akaike information criterion=7140.989, Bayesian information criterion=7485.373) defined by different preferences for the 5 attributes. In the 4-class model, out of 926 residents, 88 (9.5%) were assigned to class 1, named as the negative latent type; 216 (3.3%) were assigned to class 2, named as the positive integrated type; 434 (46.9%) were assigned to class 3, named as the positive comfortable type; and 188 (20.3%) were assigned to class 4, named as the neutral quality type. For these 4 latent classes, "out-of-pocket cost" is the most preferred attribute in negative latent type and positive integrated type residents (45.04% vs 66.04% importance weights), whereas "screening technique" is the most preferred factor in positive comfortable type residents (62.56% importance weight) and "screening interval" is the most valued attribute in neutral quality type residents (47.05% importance weight). Besides, residents in different classes had common preference for painless endoscopy, and their willingness to pay were CNY ¥385.369 (US $59.747), CNY ¥93.44 (US $14.486), CNY ¥1946.48 (US $301.810), and CNY ¥3566.60 (US $552.961), respectively. Residents' participation rate could increase by more than 89% (except for the 60.98% in class 2) if the optimal UGC screening option with free, follow-up for precancerous lesions, 45% mortality reduction, screening every year, and painless endoscopy was implemented. CONCLUSIONS: Public preference heterogeneity for UGC screening does exist. Most residents have a positive attitude toward UGC screening, but their preferences vary in selected attributes and levels, except for painless endoscopy. Policy makers should consider these heterogeneities to formulate UGC-screening programs that incorporate the public's needs and preferences to improve participation rates.

MiR-34a and endothelial biology.

MicroRNAs (miRNAs) are endogenous ∼22 nt long RNAs that play important gene-regulatory roles in cells by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. Many miRNAs have been identified in endothelial cells and play important roles in endothelial biology. miR-34a is relatively early identified in endothelial cells and has been involved in regulating endothelial functions, angiogenesis, differentiation, senescence, inflammatory response, responses to shear stress, and mitochondrial function. This review outlines the current understanding of miR-34a in endothelial biology and discusses its potential as a therapeutic target to treat vascular diseases.